Substantial progress has been achieved in recent years in understanding the underlying biophysical nature of the MR BOLD signal. Most efforts have been directed toward study of dynamic changes in the BOLD signal during changes in brain activity. At the same time, very little attention has been paid to the nature of BOLD contrast in the resting state of the brain. Such an understanding is crucial to deciphering the consequences of baseline state impairment by diseases of the brain such as stroke, Alzheimer's disease, Huntington's disease, and other neurological disorders. It can also be of great importance for evaluation of hypoxia within tumors of the brain and other organs. We have developed a quantitative biophysical model of BOLD contrast (qBOLD) in MRI that analytically connects BOLD MRI signal to hemodynamic parameters, such as deoxygenated blood volume (DBV) and oxygen extraction fraction (OEF). Our preliminary MR-measured hemodynamic parameters obtained on healthy human subjects are in a good agreement with previous determinations. To date, the most accepted in vivo measurement of OEF in clinical neurological research uses [15O] tracers and PET. To make our qBOLD- based MR technique a working tool for research and clinical applications, direct comparisons between qBOLD and PET are required. We propose to conduct these comparisons in normal healthy subjects and in subjects with a Moyamoya syndrome. This rare disorder is characterized by an obliterative vasculopathy of the large arteries at the base of the brain leading to regionally increased OEF. If we find high correlation between our MR estimates of OEF and PET measures of OEF in both healthy and pathologic conditions, we will have completed an important step in validating our qBOLD approach for neurological disease research. Normal human subjects will also be recruited to undergo both PET and qBOLD MR measurements during visual activation is known to decrease regional OEF. These data will provide complementary information with a range of OEF values not seen in the resting state. The determination that the qBOLD technique yields estimates of OEF during visual activation that are highly correlated to PET measures will be additional justification for use of our new MR method in neurological investigation of brain hemodynamics. We expect our qBOLD model will provide adequate basis for data analysis. However, we will also perform quantitative evaluation of the model limitations and will further refine the model to investigate possibility of improvements in OEF and DBV quantification. The overarching goal of this proposal is to develop a new MR-based method for the quantitative in vivo evaluation of brain hemodynamics in health and disease. When fully implemented, this will provide an extraordinary tool for cognitive studies and clinical diagnosis, one that is much more widely available to clinicians and researchers than is oxygen-15 based PET for the measurement of brain hemodynamics. The overarching goal of this proposal is to develop a new Magnetic Resonance Imaging -based method for the quantitative in vivo evaluation of brain hemodynamics in health and disease. When fully implemented, this will provide an extraordinary tool for cognitive studies and clinical diagnosis, one that is much more widely available to clinicians and researchers than is oxygen-15 based Positron Emission Tomography for the measurement of brain hemodynamics and metabolism. [unreadable] [unreadable] [unreadable]